Novel Protein-Lipid Conformations of High Density Lipoproteins through Molecular Dynamics

A detailed understanding of the lipid-associated structure of apolipoprotein (apo) A-I, the major protein of the anti-atherogenic high density lipoprotein (HDL), is crucial because the lipid environment of HDL modulates apoA-I structure and function. Recently, this lab proposed an atomic resolution double belt model for apoA-I associated with discoidal HDL, in which two apoA-I molecules were wrapped beltwise around a discoidal lipid bilayer containing 160 palmitoyloleoylphosphatidylcholine (POPC) molecules. Recently, our lab has shown that apoA-I complexed with POPC forms three different sized discoidal HDL particles containing 2 apoA-I. To understand the structure of these discrete particles, we performed molecular dynamics (MD) simulations of model discoidal HDL particles formed by systematically removing POPC molecules from an initial particle with 160 POPC and a double belt of two antiparallel lipid-associating domains of apoA-I (residues 41-243). After a few nanoseconds of MD simulation, independent of either of two starting particles and either of two methods of size reduction, the flat disc is transformed to a saddle-shaped bilayer structure approximating an Enneper’s minimal surface with the apoA-I double belt twisted to conform to the surface edge. Since POPC molecules seek to minimize their surface curvature forming flat bilayers (trivial minimal surfaces) the conversion to an Enneper’s minimal surface should involve minimal energy. Further, each of the simulated double belts forms a close approximation of the non-planar, amphipathic alpha helical structure of the X-ray structure of lipid-free apoA-I. Most importantly, the MD simulated apoA-I conformation was independent of the starting particle and the method of particle size reduction. We conclude that apoA-I represents a unique lipid-scavenging nanomachine capable of assembling variable numbers of phospholipid molecules into stable minimal surface particles.